The purpose of this project is to (a) conduct and coordinate interdisciplinary studies on members of cancer-prone families and other high-risk populations to clarify the role of genetic mechanisms and host-environmental interactions in human carcinogenesis; and (b) assess, quantify, and elucidate the determinants of the cancer risks associated with therapeutic exposure to cytotoxic drugs. Project staff also conduct or collaborate with others EEB investigators in epidemiologic case- control studies of specific cancers or cohort studies of specific exposures that are particularly relevant to this project. A series of project resources has been developed in support of our research, including (1) a computerized registry of cancer-prone families; (2) a biospecimen repository which processes, stores and distributes biological samples from persons at high risk of cancer; (3) a fibroblast repository/tissue culture facility; and (4) a series of contract-supported laboratories which provide immunologic, cytogenetic, and DNA repair assay capabilities. Persons at high risk of cancer are evaluated clinically and donate biological samples. Clinical, epidemiologic, genetic, and laboratory studies are combine to elucidate mechanisms of cancer susceptibility. The familial melanoma project is a protype of this approach, in which clinical (dysplastic nevi), genetic (autosomal dominant transmission of a gene possibly linked to the Rh locus) and biologic (enhanced sensitivity to the cytotoxic and mutagenic effects of UV radiation) risk factors have been identified. The therapeutic administration of cytotoxic drugs provides an opportunity to explore the carcinogenic effects of these agents in man. Case-control and cohort studies of cancer patients treated with specific cytotoxic drugs are conducted. These studies have documented differences in leukemogenic potential among specific alkylating agents, and increasing risk of leukemia with increasing total drug dose. In addition, increased risk of bone cancer associated with alkylating agents independent of radiation therapy has been demonstrated.